Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as human herpesvirus 8, is a member of the gamma-herpesvirus family, which includes Epstein-Barr virus (EBV) and rhesus rhadinovirus (RRV). KSHV infection is associated with all types of KS, including AIDS-associated KS, and is also implicated in B cell lymphoproliferative diseases such as primary effusion lymphoma (PEL) and multicentric Castleman's disease. The KSHV genome contains close to 80 open reading frames, some of which are homologs of other gamma herpesviruses (ORF 1 to 75), whereas others are unique to KSHV (K1 to K15). The proteins for these genes function in a variety of ways including regulation of viral replication, cell transformation, and interaction with host proteins. We previously identified by cDNA cloning, an early gene, K-bZIP (KSHV basic-leucine zipper), which is the structural and positional analogue of EBV Zta, a key regulator of viral reactivation and replication. K-bZlP. We subsequently identified a homolog, R-bZlP, in RRV, which has the same splice pattern as its counterpart in KSHV. Both K-bZIP and R-bZIP are nuclear proteins that form homodimers and regulate viral transcription and cell cycle events. K-bZIP directly interacts with, K-Rta, which is a viral transcriptional regulator that triggers lytic viral replication, and represses K-Rta activity. Importantly, our recent studies demonstrated that K-bZIP is a general gene-silencer; this activity of K-bZIP is associated with sumoylation, which is a post-transcriptional modification of transcription factors. In addition, we demonstrated that K-bZIP interacts with host cell cycle regulators to delay the G1 to S transition. Taken together, these findings support the hypothesis that K-bZIP plays a key role in altering host cell activities to thereby provide an optimal environment for the early phase of viral replication. Based on our novel observations, and equipped with new reagents and approaches developed in our recent research efforts, we propose the following two aims on the virus/host cell interaction: (1) to analyze the molecular mechanism(s) by which K-bZIP regulates host gene expression and (2) to determine the role of K-bZIP in the KSHV reactivation and replication. The results of the proposed studies will not only contribute significantly to knowledge of KSHV transcriptional regulation, but will also provide new ideas and approaches for investigating the role of transcriptional activators of other.